Vesicle trafficking is defined as the vesicular transport of materials between different subcellular compartments of eukaryotic cells. Vesicles bud from a donor membrane and fuse with a recipient one carrying internalized materials from one site to another. Rab proteins, low molecular weight guanidine triphosphatases (GTPases) of the Ras superfamily, help regulate vesicular transport by directing the vesicles to and from the correct membrane surfaces (Novick, P. and Brennwald, P. (1993) Cell 75: 597-601).
In their role as GTP transferases, Rab proteins are prenylated, bind GTP and are placed in particular intracellular membranes by escort proteins (Khosravi-Far, R. et al. (199 1) Proc. Natl. Acad. Sci. 88: 6264-6268). Experimental evidence shows that in the vesicle, GTP-bound Rab proteins interact with SNARE factors to direct vesicle transport. After transport, GTPase activating proteins in the target membrane convert Rab proteins to the GDP-bound form, and guanine-nucleotide dissociation inhibitor helps return the GDP-bound protein to its membrane of origin.
Evidence indicates that pancreatic acinar cell enzyme secretion may be regulated by Rab proteins. Wagner, A. et al. (1995, Biochem. Biophys. Res. Comm. 27: 950-956) used a Rab 3A probe to screen a rat pancreatic cDNA library and identified Rab 26, a new 190 amino acid member of the Rab protein family. Rab 26 contains conserved GTP-binding regions and C-terminal isoprenylation sites characteristic of the Rab protein family members. Northern analysis of Rab 26 demonstrated expression in kidney, brain, salivary gland, lung, and pancreas. The authors speculate that Rab 26 might be involved in the vesicle trafficking which regulates pancreatic secretion.
To date, more than 30 Rab proteins have been identified, and each may have a characteristic intracellular location where it functions in distinct, tissue-specific transport events. Some examples of Rab proteins, their functions, and implication in disease processes are summarized. Rab3A is a component of brain synaptic vesicles and has been implicated in the regulation of neurotransmitter release. Overexpression of Rab proteins significantly enhances the function of Rev, a viral gene essential for processing HIV-1 (Fridell, R. A. et al. (1996) Proc. Natl. Acad. Sci. 93: 4421-4424). A deficiency in the prenylation of one particular Rab is associated with choroideremia, a form of retinal degeneration that causes blindness. Interaction between Rab protein and Cdc2 protein kinase in vitro inhibited vesicle fusion and implicated Rab protein function in mediating cell cycle events (Toumikoski, T. et al. (1989), Nature 342: 942-945). Thus, Rab proteins appear to be involved in the complex and critical processes of vesicle trafficking for the directed release of various molecules including digestive enzymes and signaling molecules, for viral processing, and in mitotic and meiotic cell cycle.
The discovery of polynucleotides encoding novel Rab proteins and the molecules themselves satisfy a need in the art by providing new compositions useful in the diagnosis, prevention, or treatment of disorders associated with vesicle trafficking, viral infection, and cancer.